A promising new approach in battling Alzheimer’s disease has emerged, involving an innovative nasal spray drug that targets a specific brain enzyme. Researchers at Università Cattolica and Fondazione Policlinico Universitario A. Gemelli IRCCS have discovered that inhibiting the enzyme S-acyltransferase (zDHHC) with this nasal spray can counteract cognitive decline and brain damage typically associated with Alzheimer’s. Led by Professor Claudio Grassi and Professor Salvatore Fusco, the research team found that Alzheimer’s patients have an excess of this enzyme, which correlates directly with worsening cognitive performance. This significant finding has identified S-acyltransferase as a potential drug target, bolstered by a substantial €890,000 grant from the Ministry of Health’s 2023 PNRR call.
Understanding Alzheimer’s Disease Development
Protein Alterations and Cognitive Decline
Alzheimer’s disease is primarily driven by several protein alterations, notably the accumulation of beta-amyloid plaques and tau tangles within the brain. These proteins are regulated by various biochemical signals and modifications, with one significant process being S-palmitoylation carried out by S-acyltransferase enzymes, particularly zDHHC. Prior studies have suggested that altered S-palmitoylation of synaptic proteins plays a crucial role in cognitive decline observed in metabolic diseases such as type 2 diabetes. Specifically, brain insulin resistance may influence zDHHC enzyme levels, setting the stage for similar mechanisms in Alzheimer’s.
In their current research, the scientists demonstrated that early-stage Alzheimer’s disease involves molecular changes that reflect brain insulin resistance. This condition increases the levels of the zDHHC7 enzyme, which consequently alters the S-palmitoylation of proteins vital for cognitive function and the accumulation of beta-amyloid. According to lead author Dr. Francesca Natale, inhibiting protein S-palmitoylation in animal models of Alzheimer’s effectively counteracted the harmful protein accumulation within neurons, thereby delaying both the onset and progression of cognitive decline. Post-mortem brain analyses from Alzheimer’s patients showed elevated levels of zDHHC7 and S-palmitoylated proteins, with a direct correlation between the S-palmitoylation levels of BACE1 and patients’ cognitive performance scores.
Nasal Spray and Enzyme Inhibition
Experiments using genetically modified mice that model Alzheimer’s disease further highlighted the potential of enzyme inhibition as a therapeutic strategy. Researchers utilized a nasal spray drug called “2-bromopalmitate” to deactivate zDHHC enzymes. Remarkably, this intervention successfully halted neurodegeneration in the mice, reduced Alzheimer’s symptoms, and extended their lifespan. Despite these promising results, Professor Grassi emphasized that no current drugs are available that can selectively block zDHHC7, highlighting a significant challenge. Additionally, 2-bromopalmitate is not highly selective, pointing to the need for more precise drug development.
The PNRR 2023 funding aims to support the exploration of novel therapeutic approaches that may be applicable to human treatments. This includes the potential development of genetic patches or engineered proteins designed to interfere specifically with zDHHC enzyme activity. By doing so, researchers hope to pave the way for more effective and targeted therapies for Alzheimer’s disease, moving beyond the limitations of current treatments.
The Future of Alzheimer’s Treatment
Next Steps and Potential Human Applications
This groundbreaking research points to new therapeutic directions that focus on enzyme inhibition, opening up new possibilities for combatting Alzheimer’s disease. The identification of S-acyltransferase as a promising drug target sets the stage for the development of innovative treatments that could potentially reverse or halt the progression of the disease. With continued funding and research, the next steps involve translating these findings from animal models to human applications, which could revolutionize the current approach to Alzheimer’s treatment.
Exploring the potential of enzyme inhibition therapies may involve designing drugs that can precisely target and modulate the function of zDHHC enzymes. This could include the use of genetic techniques to create “patches” that can correct enzyme functionality or the engineering of proteins that can specifically interfere with the activity of harmful enzymes like zDHHC7. The goal is to develop therapies that can precisely and effectively address the molecular root causes of Alzheimer’s, offering hope for patients and their families.
Broader Implications for Neurodegenerative Diseases
Alzheimer’s disease is driven by protein changes, notably beta-amyloid plaques and tau tangles in the brain. These proteins are influenced by various biochemical signals, including S-palmitoylation, a process executed by S-acyltransferase enzymes like zDHHC. Prior studies indicate that altered S-palmitoylation of synaptic proteins is crucial in cognitive decline in metabolic diseases such as type 2 diabetes. Brain insulin resistance may affect zDHHC enzyme levels, hinting at a similar mechanism in Alzheimer’s.
Recent research reveals that early-stage Alzheimer’s involves molecular changes mirroring brain insulin resistance. This condition elevates zDHHC7 enzyme levels, altering the S-palmitoylation of proteins essential for cognitive function and contributing to beta-amyloid accumulation. Dr. Francesca Natale stated that inhibiting protein S-palmitoylation in animal models of Alzheimer’s successfully countered harmful protein build-up in neurons, delaying cognitive decline. Post-mortem analyses of Alzheimer’s patients’ brains showed elevated zDHHC7 and S-palmitoylated protein levels, with a direct link between S-palmitoylation levels of BACE1 and cognitive performance scores.
